Title: APOE as a modifier of prion-like spread in dementia Abstract: The overall objective of this multidisciplinary project is to test the hypothesis that relative to APOE2 or APOE3, APOE4 facilitates the seeding and spread of misfolded A?, tau, and ?-synuclein (?Syn). Inheritance of an APOE4 allele increases the risk of developing Alzheimer's disease (AD) dramatically. Most studies suggest that the primary mechanism by APOE increases the risk for AD is by modulating the deposition of A? peptide. However, there are studies that suggest APOE may also directly modulate the phosphorylation and misfolding of tau. Although APOE genotype is not recognized as a risk factor allele for the pure ?Syn-opathies, such as Parkinson's disease (PD) the presence of an APOE4 allele has been shown to increase risk of dementia in PD by some studies. In vitro, APOE can directly modulate the aggregation of ?Syn. Somewhat surprisingly, although the first descriptions of A? seeding in mice were reported more than 10 years ago and various human APOE models have been available for many years, there have been no studies of how APOE genotype may modulate seeding of A?. Similarly, there has been no study of how APOE genotype may influence tau or ?Syn seeding. We now propose three Aims to conduct a thorough and systematic assessment of how different isoforms of human APOE impact the prion-like seeding of A?, tau and ?Syn, with focus on assessing whether different APOE isoform may interact with these aggregating proteins to produce distinct strains of misfolded A?, tau, or ?Syn. Aim 1 will determine the relative ability of APOE2, APOE3 and APOE4 to support the seeding of A? pathology, and whether APOE isoform modulates the strain characteristics of the seeded A? aggregates. Aim 2 will determine whether ApoE genotype influences the severity or spread of CNS tau pathology. Aim 3 will determine the impact of ApoE genotype on the seeding and transmission of ?Syn. Collectively, these studies will produce a unique repertoire of animal models and provide the first assessment of whether different human ApoE isoforms may be influencing that pathogenesis of AD and DLB by modulating the prion-like seeding of amyloid, tauopathy, and ?-Synopathy.